The breast cancer susceptibility gene 1 (Brca1) plays a key role in both hereditary and sporadic mammary tumorigenesis. However, the extent to which BRCA1-activated molecular pathways contribute to its tumor suppressor activity also remains unclear. Activation of AKT kinase is one of the most common molecular alterations associated with human tumors. Increased AKT kinase activity is reported in most of the breast cancers. Our preliminary data indicate that down-regulation of BRCA1 expression or mutations of the Brca1 gene activate the AKT1 oncogenic pathway. BRCA1 directly binds to AKT1 kinase and down-regulates its activation through the ubiquitination-protein degradation pathway. Moreover, the mutant of AKT1 induced the cell growth is dependent of that it lacks the interaction with BRCA1. In human breast cancers, reduced expression of BRCA1 is correlated with increased phosphorylation of AKT1. These results support the hypothesis that the activation of AKT1 is involved in BRCA1-deficiency mediated tumorigenesis. The specific aims of the proposed studies are: (1) To establish the molecular details of the BRCA1-AKT1 pathway; (2) To understand the contributions of BRCA1-AKT1 pathway to tumorigenesis; and to establish the AKT1 pathway as novel preventive and therapeutic targets for BRCA1-deficient cancers. To achieve these goals, a series of studies is planned which will: 1) Determine the molecular mechanism of BRCA1 regulating AKT1 activation and investigating the functional effects of the direct interaction of BRCA1 with AKT1; 2) Generate a knock-in mouse with AKT1 mutation that fails to interact with BRCA1 and define the role of BRCA1-AKT1 pathway in tumorigenesis; 3) Target mTOR, a critical downstream effector of AKT1, to determine whether the AKT1 pathway is a novel target for the prevention and treatment of BRCA1-deficient cancers. Thus, the proposed studies in this application will generate strong evidence that AKT1 activation is regulated by BRCA1 in vivo. The Akt1 mutant mouse model will be useful new tool for studies of the BRCA1/AKT1 pathway in tumorigenesis and cancer therapy. PUBLIC HEALTH RELEVANCE: Establishment of the novel BRCA1-AKT1 pathway in cancer development and elucidation of its precise molecular functions are expected to improve our understanding of hereditary as well as sporadic cancer formation. The studies proposed in the application should make significant contributions to the field of breast cancer prevention and therapy.